The proposal describes a five-year mentored laboratory training experience designed to lead to an independent academic career in clinically-relevant basic science. The applicant holds M.D. and Ph.D. degrees, and is completing specialty training, leading to board certification, in Medical Genetics. The career development plan includes mentored research training which will comprise learning new research techniques and concepts supplemented by didactic training, seminars, grant-writing workshops, lab meetings, journal clubs, presentations at national/international meetings, an advisory committee and regular meetings with the mentors. The research environment provides the best intellectual environment and technology available and gives the applicant the opportunity to be guided in learning adipose and mitochondrial biology and patient oriented research. The research seeks to take insights provided by patients suffering from a rare genetic disease that leads to extreme thinness into the laboratory in order to unravel the mechanism by which such a phenotype is produced. In that, it is an example of bedside- to-bench basic science that has the potential to inform far commoner diseases such as obesity, metabolic syndrome and diabetes. The patients have all been identified to have distal, heterozygous, truncating mutations in FBN1, which encodes for Fibrillin-1, an extracellular matrix protein that is associated with Marfan syndrome. The patients have much greater than normal caloric intake, and there is no evidence of excessive physical activity or steatorrhea, suggesting enhanced mitochondrial uncoupling as a means for loss of energy. FBN1 is expressed highly in white adipose tissue and its expression changes robustly upon manipulation of fat cells in vitro and in vivo. Adipose tissue derived from C-terminal truncation mutant fibroblasts, compared with WT, displays a gene expression profile consistent with turning off of the white adipose program in favor of the brown/beige adipose program, including a large increase in UCP1, which is a marker of uncoupled respiration. This provides a plausible avenue for unabated energy loss potentially leading to extreme thinness. The proposed research will define the mitochondrial phenotype of C-terminal truncation mutant fibroblasts and derived adipocytes, and will test the predicted increased metabolic rate in affected patients. The mechanistic basis for this phenotype will then be explored by defining the mRNA and protein product of the mutant allele followed by establishing whether haploinsufficiency of the missing polypeptide or dominant negative/neomorphic effect of the mutant protein is responsible for the effect. This research will create a broader understanding of the development of white and beige adipose tissue and associated mitochondrial biology. This could have clinical implications, and has the potential to provide new therapeutic targets, against obesity, metabolic syndrome and other highly prevalent comorbidities associated with energy excess. This research will occur in an environment dedicated to training the applicant to pursue this research further as an independent scientist.